The present invention relates to the preparation of ruthenium-based catalysts for metathesis, in particular to the synthesis of Ru-based metathesis catalysts, which comprise a chelating alkylidene ligand (so called “Hoveyda type” catalysts). The catalyst preparation method is based on a cross metathesis reaction in the presence of a polymer-supported cation exchange resin acting as a ligand scavenger. The method of the present invention is simple, straightforward, environmentally friendly and provides high yields.
Olefin metathesis is a fundamental catalytic reaction and one of the most versatile ways to make carbon-carbon bonds and build molecules. Various metathesis reaction pathways are known, such as ring-closing metathesis (RCM), ring-opening metathesis polymerization (ROMP), cross metathesis (CM) and their combinations. In the past years, olefin metathesis has become a widely used method for the formation of carbon-carbon bonds in organic synthesis and polymer chemistry. The development of well-defined ruthenium-based carbene catalysts by Schrock and Grubbs has led to a fast growth in the field of metathesis, particularly for industrial applications.
The Grubbs-type “first generation” catalyst, a ruthenium benzylidene complex with two tricyclohexylphosphine ligands, having the structure (PCy3)2Cl2Ru═CHPh (ref to Scheme 1; catalyst 1a was one of the first metathesis catalyst widely used in organic synthesis. It was followed by a more active “second generation” analog, in which N-heterocyclic carbene (NHC) ligands, such as “saturated” SIMes (=1,3-dimesityl-imidazolidine-2-ylidene) replaces one tricyclohexylphosphine (PCy3) ligand (catalyst 1b).
Recently, the so-called “Hoveyda-type” catalysts are gaining increased importance. Hoveyda et al. disclosed latent metathesis catalysts based on a benzylidene-ether fragment connected to an alkylidene (carbene) moiety (ref to S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, J. Amer. Chem. Soc. 2000, 122, 8168-8179) and WO 02/14376 A2. These type of Ru-catalysts comprise chelating alkylidene ligands (typically alkoxybenzylidene ligands) and either a PCy3 ligand (first generation, catalyst 3a) or a NHC ligand (second generation, catalyst 3b). The cyclic benzylidene moiety and the chelating donor group may be further substituted.
The development of well-defined ruthenium catalysts has rendered olefin metathesis an efficient and reliable tool for the formation of carbon-carbon double bonds. The Grubbs-type catalysts 1a and 1b have found various applications in synthetic chemistry and the ruthenium indenylidene type catalysts 2a and 2b have proven to represent splendid alternatives. Hoveyda-type catalyst 3a and its phosphine-free congener 3b exhibit enhanced activity in various metathesis reactions compared to catalysts 1 and 2 and hold as a benchmark for further catalyst development.

Ru-indenylidene catalyst 2c was described recently by D. Burtscher, C. Lexer et al (ref to J. of Polymer Science, Part A: Polymer Chemistry 2008, Vol. 46, 4630-4635). Over the past years, Hoveyda-type catalysts with functional substituents at the aryl bridging group have been developed (ref to catalyst 3c). As an example, catalyst 3d, bearing a keto-group in the O-containing side chain, is described in WO 2008/034552.
The Hoveyda-type catalysts exhibit a broader application profile in metathesis reactions and allow to reduce the catalyst loading in some applications considerably. In some cases, these compounds can form latent catalyst species and are reported to be partially recyclable. Therefore, this type of catalysts is important for commercial applications. Consequently, appropriate catalyst manufacturing processes are required, which allow economical production in industrial scale.
The general preparation route for Hoveyda-type catalysts is based on the use of ruthenium carbene complexes of the type X2L1L2Ru═CHPh (wherein L1 is a neutral 2-electron donor and L2 preferably is a phosphine of the type PPh3 or PCy3) as starting complexes. These compounds are reacted with suitable styrenylether precursor ligands, which comprise an additional donor group. The new carbene bond is generated by cross metathesis reaction (“CM”), while one phosphine ligand is replaced by the donor group of the styrenylether ligand, thus forming a chelating ring complex.
More specifically, the Hoveyda-type catalysts 3a and 3b are generally prepared from reaction of 1a/b or 2a/b with 2-isopropoxystyrene in presence of copper(I)chloride (CuCl). In this reaction, CuCl acts as a phosphine scavenger, shifting the reaction towards closure of the κ2-(C,O)-chelate. Unfortunately, CuCl is easily oxidized in presence of atmospheric oxygen which complicates handling during preparation of metathesis catalysts and during long-term storage. In addition, application of excess CuCl requires specific workup since it can not be quantitatively retained using column chromatography. Although alternative procedures have been reported in the literature, these methods require multiple preparative steps and/or post-end column chromatography.
S. Gessler, S. Randl and S. Blechert (Tetrahedron Letters 2000, 41, 9973-9976) report a 2-step procedure for preparation of catalyst 3b based on the exchange of PCy3 by SIMes when starting from catalyst 3a. The product was purified by chromatography in 75% overall yield. Due to the multiple steps involved, this route is not commercially feasible.
A. Fuerstner, P. W. Davies and C. W. Lehmann (Organometallics 2005, 24, 4065-4071) report the preparation of bidentate ruthenium vinylcarbene catalysts derived from standard metathesis catalysts by enyne metathesis with phenylacetylene derivatives.
M. Bieniek, A. Michrowska, L. Gulajski and K. Grela (Organometallics 2007, 26, 1096-1099) describe a 2-step preparation method for the nitro-substituted Hoveyda-type catalyst 3c, using a metathesis exchange reaction.
S. Blechert et al. (Synlett 2001, 3, 430-432) report the use of a SIMes- and PPh3-substituted Ru-indenylidene complex as a precursor for the preparation of catalyst 3b by cross metathesis with a phenylether. The product was purified by column chromatography. Yields of 40% are reported, thus this method seems not to be economical.
M. Barbasievicz et al. (Organometallics 2006, 25(15), 3599-3604) report the synthesis of chelating ruthenium quinoline and quinoxaline complexes starting from the Grubbs-type catalyst 1b (SIMes)(PCy3)Cl2Ru═CHPh and using Cu(I)Cl as phosphine scavenger.
WO 2004/112951 describes the preparation of ruthenium-based olefin metathesis catalysts by a cross metathesis reaction using Ru-indenylidene carbene complexes and an olefin. The preparation of Hoveyda-type catalysts comprising chelating alkylidenes is not disclosed.
U.S. Pat. No. 7,026,495 and US 2009/0088581 are related to chelating carbene ligand precursors for the preparation of olefin metathesis catalysts. Methods of preparing Hoveyda-type catalysts without the use of copper(I) chloride are disclosed. Organic acids, mineral acids (such as HCl), mild oxidants (such as bleach) or even water are employed. When employing gaseous HCl, yields of 82% for catalyst 3b are reported. Still, precipitation, separation and purification steps are needed in these methods. Furthermore, excess acid cannot be removed and thus remains in the reaction mixture.
In summary, despite considerable research in the field, the preparation methods for Hoveyda-type metathesis catalysts still suffer from various drawbacks. The synthesis routes starting from the Grubbs-type catalysts 1a and 1b usually employ hazardous chemicals, such as diazo reagents (e.g. diazoalkenes) for the preparation of the educt complex. Furthermore, precipitation, separation and purification steps (such as column chromatography etc) are needed in these methods. Finally, the yields and the purity of the resulting products need to be improved.
It was therefore an objective of the present invention to provide an improved process for preparation of ruthenium-based carbene catalysts with chelating alkylidene ligands (“Hoveyda-type” catalysts). The new method should not employ CuCl as a phosphine scavenger and should not require time-consuming isolation and/or purification steps. Furthermore, the method should provide the ruthenium carbene catalysts in high yields and high product purity (i.e. without residues of phosphine ligands, phosphine oxides or Cu ions). Finally, the method should be clean and simple, easily scalable, environmentally friendly, inexpensive and applicable to commercial, industrial scale.